A-nor derivatives of the pregnane series and intermediates in the production thereof



. 70,919 A-NOR DERIVATIVES OF THE PREGNANE SE- RIES AND INTERMEDIATES IN THE PRODUC- TION THEREOF Josef Fried, Princeton, N.J., assignor to Olin Mathieson Chemical Corporation; New York, N.Y., a corporation of Virginia No Drawing. Filed July 24, 1962, Ser. No. 212,154 31 Claims. (Cl. 260-2395) This invention relates to, and has for its objects, the provision of new physiologically active steroids, methods for preparing the same, and new intermediates useful insaid preparation.

The products of this invention can be represented by the formulae CHgZ' CHgZ i /i O- CHZZ CHQZ CH Z =0 =0 /\l /i OJ 7 CHzZ l z :0 (3:0

wherein Z may be hydrogen, hydroxy, halogen (i.e'., chloro, fluoro, iodo or bromo) or acyloxy; R is hydrogen; R' may be hydrogen or hydroxy; or together R and R is oxo (0 The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic,

nited States Patent 0 propionic, butyric, and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoi'c and toluic acid), the monocyclic aryl' lower alkanoic acids (e.g., phenacetic and fi-phenyl'propionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

[In this application and in the appended claims; whenever, in the formulae set forth herein, a curved line (2) is employed in the linkage of atoms, it is meant to denote that the connected atom may be either in the alpha or beta position, as is determined in the respective compounds involved] Those final products of this invention which are unsubstituted in the 2l-position (i.e., Z is hydrogen or halogen) are physiologically active compounds which possess progestational activity and thus can be employed insteadofprogesterone, for example, in the treatment of habitual abortion for which purpose they can be administered in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid. Those final products of this invention which are oxygenated in the 21-position (i.e., Z is hydroxy or a'cyloxy) are physiologically active compounds which possess mineraloeorticoid activity and thus can be'employed instead of desoxycorticosterone, for example, in the treatment of Addisoris disease, for which purpose they can be administered in the same manner as desoxycorticosterone, for example, the dosage being adjusted for the relative potency of the particular steroid.

In addition, it has been found that the compounds of this invention are physiologically active steroids which possess antiandrogenic activity, i.e., they inhibit the action of androgens, and they can be used in the treatment of such conditions as hyperandrogenic acne. The compounds may be formulated for such administration, the concentration and/or dosage being based on the activity of the particular compound and the requirements of the patient.

The final products of this invention are prepared by the process of this invention which entails a number of steps beginning with a triterpenoid acid as a starting material. By a-triterpenoid acid, it is here" meant a polymethylsteroid, having a D-ring structure represented by the formula:

wherein R may be the same or difierent and may be either hydrogen or alkyl and R may be the same or dilferent and may be selected from the group consist ing of hydrogen and hydroxyi Examples of the triterpenoid acids which may be employed in the practice of this invention include eburicoic, polyporenic, tumulosic, pinicolic, elemolic, elemonic, dehydroeburicoic, dehydroelemolic, dehydroelemonic, and other like acids. The steps of the process (employing eburicoie acid. as the starting material) are shown by the following equations wherein R and R are the same or different and represent hydrogen or acyl, and R" represents acy1;-Z repre- CH Z XLI. Z=halide (Cl, Br, F or I) XLII. Z=CH3COO XLIII. Z=OH XLIV. Z=H

In the first step of the process of this invention eburicoic acid is converted to its S-ester derivative (Compounds A) The 3-acetate of eburicoic acid is a known compound. Other 3-esters can be prepared in the usual manner by reacting with the desired acylating agent (e.g., acyl chloride or acid anhydride) in the presence of a base, such as pyridine. Although any ester can be prepared, the preferred esters are those with hydrocarbon carboxylic acids of less than twelve carbon atoms. These are formed by reacting with the acyl chloride or acid anhydride of a hydrocarbon carboxylic acid of less than twelve carbon atoms, such as one of the acids listed hereinbefore.

The 3-ester is then converted to a corresponding ester of 24-keto-A -lanostene-2l-oic acid (Compounds C). This may be done by ozonolysis of Compounds A and reducing the ozonide formed by treatment with either hydrogen in the presence of a hydrogenation catalyst, such as palladium or charcoal, or an electropositive metal, such as zinc, in the presence of an acid, such as glacial acetic acid, whereby Compounds C are obtained directly. Compounds C can also be obtained in a two-step process by first treating Compounds A with a hydroxylating agent, such asosmium tetroxide, to yield the corresponding 3- ester of 3/3,24,-28-trihydroxy-A -eburiCene-Zl-oic acid (Compounds B) and then cleaving the glycol, as by treatment with lead tetraacetate to yield Compounds C.

Compounds C are then lactonized by treatment with an acid anhydride and a salt of a strong base and a weak acid, such as sodium acetate in acetic anhydride, to yield a mixture of the a-lactone (Compounds D) and p-lactone (Compounds E) of the corresponding 3-esters of 35- hydroxy-24-keto-A -lanostene-2l-oic acid. The reaction is preferably carried out at an elevated temperature, such as the reflux temperature of the organic solvent employed and the two lactones are separated chromatographically. However, since both the a-lactone and fi-lactone give the same product in the next step of the process of this invention, suchseparation is not necesary and a mixture of the lactones may be used directly.

Compounds D and E are then dehydrogenated, as by treatment with palladium on charcoal at an elevated temperature, to yield the corresponding 3-ester of 3fi,24-dihydroxy-A -lanostatriene-2l-oic acid lactone (Compounds F).

Compounds F can then be isomerized to the corresponding 3 acetoxy-24-hydroxy-A -1anostatriene- 2l-oic acid lactone derivative (Compounds G), by treatment with hydrogen chloride in a solvent (e.g., glacial acetic acid).

The lanostatriene 21-oic acid lactones (Compounds F and G) may then be oxidized by treatment with potassium permanganate, and the manganese dioxide formed, reduced as by treatment with sulfur dioxide, to form the A -5e-androstene-7,11 dione 17,6 carboxylates (Compounds H), which are new compounds of this invention.

Compounds H are then reduced as by treatment with zinc in glacial acetic acid, preferably at elevated temperatures of yield the 5u-androstane-7,l1-dione-17/3-carboxylates (Compounds I), which are also new compounds of this invention.

Compounds I are then converted to the ll-keto-Saandrostanes (Compounds L) by treatment first with an alkylenedithiol, such as ethanedithiol, in the presence of a Lewis acid, such as borontrifluoride etherate, to produce the dithioethylene ketals (Compounds K). Compounds K may then be treated at elevated temperatures with a sponge nickel catalyst in an organic solvent (e.g., ethanol) to produce Compounds L, which are new compounds of this invention.

Alternatively, Compounds L may be obtained by treating Compounds I with hydrazine and a base, such as potassium hydroxide, at elevated temperatures. In addition to the reduction of the 7-keto group, there occurs hydrolysis of the ester groups at C and C and the latter are reformed by treatment first with an acylating agent such as acid anhydride or acyl chloride, in the presence of a base, such as pyridine, followed by treatment with a methylating agent (e.g., ethereal diazomethane), to produce Compounds L directly.

The ll-kBtO-Sot-fllldIOStElIlfiS (Compounds L) may then be dehydrated and rearranged as by treatment with phosphorus pentachloride at reduced temperature in the absence of light, to yield the 3-alkylene-1l-keto-A-nor-Sw androstanes (Compounds M), which are also new compounds of this invention.

Compounds M are then treated with ozone and the ozonide formed is reduced, as by treatment with zinc and glacial acetic acid to yield the 3,11-dik6t0-A-I10f-5ocandrostanes (Compounds N) (wherein R is SaH and R is CH which are also new compounds of this invention.

These Compounds N (wherein R is 5041i and R is CH may then be hydrolyzed, as by treatment with alkali such as potassium hydroxide at elevated temperatures, to formthe free acid compounds with simultaneous epimerization at the C position, thus yielding Compounds N (wherein R is 5,8H and R is H), directly. Alternatively, these free acid compounds may be obtained in a stepwise process which entails first, treatment of Compounds N (wherein R is SaH and R is CH with cold alkali to produce Compounds N (wherein R is 55H and R is CH followed by treatment with hot alkali to yield Compounds N (wherein R is 551-1 and R is H) Compounds N may then be treated with anacid halide, for example, oxalyl chloride, to obtain the A-nor-SB-androstane-l7fl-carboxylic acid halides (Compounds 0), which are also new compounds of the instant invention.

Compounds 0 are then treated with a methylating agent, for example, ethereal diazomethane to produce 2l-diazo- ZO-keto-A-nor-pregnanes (Compounds P) which are new compounds of this invention.

In order to obtain the final products of this invention which are oxygenated in the 2l-position (i.e., Z is acyloxy or hydroxy), Compounds P are treated at elevated temperature with a fatty acid, such as acetic, propionic or butyric acid, to yield the 2l-esters of 3,l1,20-triketo-A- nor5,B-pregnane (Compounds Q) which are also new compounds of this invention. Alternatively, Compounds Q (wherein Z is acyloxy) may be obtained by first treating Compounds P with a hydrohalide, such as hydrochloric acid, to yield the 2l-halogenated A-norpregnanes (Compounds Q), which are also new compounds of this invention, and then acylating the 2l-halide A-norpregnanes as by treatment with potassium acetate and potassium iodide to yield the 2l-acyloxy-A-norpregnanes (Compounds Q). To obtain the 2l-hydroxy A-norpregnanes (Compounds Q), the 2l-acyloxy compounds are treated with a base, such as potassium carbonate. The 2l-hydroxy A-norpregnanes (Compounds Q) are also new compounds of this invention.

Compounds Q are then brominated as by treatment with bromine in an acid medium to yield the 21-oxygenated S-bromo-A-norpregnanes (Compounds R), which are also new compounds of this invention; The 2l-oxygenated S-bromo-A-norpregnanes (Compounds R) are then converted to the 21-oxygenated-A-nor-M-pregnenes (Compounds S) by treatment with a base, such as co11i dine or lithium halide, e.g., lithium chloride or lithium bromide in dimethylformamide. Compounds S are new final products of this invention.

To obtain the final compounds of this invention, which are not oxygenated in the 21-position (i.e., wherein Z is halide or hydrogen), Compounds P are first treated with a hydrohalide, such as hydriodic acid, to yield the 21- unsubstituted A-norprcgnanes (Compounds Q), which are new compounds of this invention. The 21-unsubstituted pregnanes (Compounds Q) are then brominated, as by treatment with bromine in an acid medium, to yield the ill-unsubstituted S-bromo-A-norpregnanes (Compounds R), which are then converted to the 2l-unsubstituted A-nor-A -pregnenes (Compounds S) by treat ment with a base, such as collidine or a lithium halide, such as lithium chloride, in dimethylformamide. These are also new compounds of the instant invention.

The final products of this invention which are halogenated in the 2l-position (i.e., wherein Z may be chlorobromo-fluoro or iodo) are obtained by first treating, at reduced temperatures, the Zl-diazoketone (Compounds P) with a hydrogen halide such as hydrogen chloride, to yield the corresponding 21-halo substituted A-norpregnanes (Compounds Q), which are also new compounds of this invention. The 2l-halo substituted compounds are then brominated as by treatment with bromine in an acid medium, and the resultant S-bromo-Zl-halo-A-norpregnanes (Compounds R) are dehydrobrominated as by treatment with lithium halide in dimethylformamide to yield the 2l-halo-A-nor-A -pregnenes (Compounds S), which are new final products of the instant invention.

The new final products of this invention may also be obtained by alternate procedures which may be represented by the following equations, wherein R, R, and Z are as hereinbefore defined.

0012 TU i g no XLVIII. R=H; Z=halide (DOOR ooon o J 0:? g Ozflj n w v LIII. R=OH3 XLIX. R=c1-n Lrv. R=H L. R=H

302 0 01 /5 K i 0= o- J l AA DD LV. Z=halide LVII. Z=halide CHN: CHN2 $=O (1:0 O/\i fi /i fl i O: O

BB EE LVI. Lvnr.

on z CHZZ =0 i=0 f /i 5 LL of s FF XLI. Z=l1alide o1, Br, F, or I) LIX. Z=halide e1, Br, r or 1 XLn. z=o1nooo LX. Z=oH3ooo XLIII. z=0n LXI. Z=OH XLIV. z=n LXII. z=n

In the first step of the alternate procedure which may be employed to obtain the final products of this invention, the 3,1l-diketo-A-norandrostanes (Compounds N) are treated with an enol ester of a carbocyclic acid of less than 10 carbon atoms of an aliphatic or alicyclic ketone, such as isopropenyl acetate in the presence of a strong acid, e.g., p-toluenesulfonic acid, to produce the 11-keto-A-nor-A -androstenes (Compounds T), which are also new compounds of this invention. Compounds T may then be halogenated, as by treatment with a halogenating agent, such as N-bromoacetamide, N-bromosuccinimide, dibromodimethylhydantoin, bromine, N-chloro- COZ 9 succinimide or N-iodoacetamide, to yield the -halo-'3,11- diketo-A-nor-Sfl-androstanes, (Compounds U), which are also new compounds of this invention.

Dehydrohalogenation of Compounds U, as by treatment with lithium bromide in dimethylformamide or collidine, yields a mixture of the unsaturated steroids, A- nor-A -androstenes (Compounds W) and A-nor-A -androstenes (Compounds V), both of which are new compounds of this invention. The mixture of these com pounds may be separated into the individual components (Compounds V md Compounds W), by fractional crystallization, in order to further process the individual compounds to obtain the additional products of this invention. In addition to the foregoing, an alternative method may be employed to obtain Compounds W, which first entails treating Compounds N with bromine in an acid medium, such as glacial acetic acid, to obtain the 5a-halo-A-nor-Su-andmstanes (Compounds Z) which are new compounds of this invention. Compounds Z may then be dehydrohalogenated as by treatment with lithium bromide in dimethylformamide or collidine to yield the A-nor-A -androstenes (Compounds W).

Compound W and V may then be converted to the final A-nor-pregnene derivatives of this invention by an identical series of steps. If a compound W is employed, the final product and all the intermediates thereof contain a double bond in the 5,6position. If a Compound V is employed, the final products and all intermediates contain a double bond in the 1,2-position.

In the first of this series of steps, Compounds W and V (R=I-I) are treated with an acid halide, for example, oxalyl chloride, to obtain the corresponding Amer-A androstene-lZB-carboxylic acid halides (Compounds AA) and the A-nor-A -androstene-l7,8-carboxylic acid halides (Compounds DD), respectively. These are also new compounds of this invention. These compounds are then converted to their respective diazoketone-A-norA -pregnenes (Compounds BB) and diazoketone-A-nor-A -pregnenes (Compounds EE) derivatives as by treatment with an ethereal solution of diazomethane.

Compounds BB and Compounds EE are then converted to the 21-substituted final products of this invention as set forth hereinbefore in the treatment" of Compounds P to produce Compounds S and Compounds FF, which are new final products of this invention. Thus, treatment of Compounds EE with a fatty acid, such as acetic, propionic or butyric acid yields the 2l-esters of the A-nor-n -pregnenes (Compounds FF), which are new final products of this invention. Treating Compounds EE with a hydrohalide, such as hydrogen chloride, yields final products of this invention which are 2l-halo substituted and are also new final products of this invention. The 2l-unsubstituted derivatives are obtained by treating Compounds BB and EE with hydroiodic acid, thus yielding the A-nor-A -pregnenes (Compounds S) and the A-nor-A -pregnenes (Compounds FF), which are new compounds of the instant invention.

In addition, the 2l-unsubstituted (i.e., Z is H), saturated final products of this invention may be obtained by an alternate procedure, which may be represented by the following equations, wherein R, R and Z are as hereinbefore defined:

M XXIII. R =H C C LXIII. Z=halide omz buzz In the first step of this alternate process, Compounds M (wherein R is H) are treated with an acid halide, for example, oxalyl chloride, to produce the B-aIkylene-A- nor-5a-androstane-l7B-carboxylic acid halides (Compounds CC), which are also new compounds of this invention. Compounds CC are then treated wih an ethereal solution of diamethyl cadmium to yield the 3-alkylene- A-nor-5a-pregnane-11,20-diketones (Compounds GG) which are also new compounds of this invention. Compounds GG are then ozonized to yield the A-nor-Sa-pregnane-3,1 1,20-triketones (Compounds HH) which are also new compounds of this invention. Compounds HH may then be treated with a base, such as sodium hydroxide to yield the A-nor-SB-pregnane-Iid1,20-triketones (Compounds Q, wherein Z is H), which are new compounds of this invention.

Additionally, further new products of this invention may be obtained by alternate procedures,employing the same or derivative starting material therefrom. The starting material employed in obtaining the further products of this invention is derived'from the triterpenoid acid starting material disclosed hereinbefore. The derivative employed in this alternate process is reacted'according to the equations set forth below.

The following equations represent additional alternative processes which may be employed in the practice of the invention to yield further new products, wherein R, R and Z are as hereinbefore defined:

COOR' as mp In the first step of this alternate procedure, Compounds I (wherein R=CH CO and R=CH are reduced as by the Wolff-Kishner reduction process, employing hydrazine and potassium hydroxide at elevated temperatures to yield the 3-acetoXy-5a-androstane-17fl-carboxylate (Compounds 1]) which are new compounds of this invention.

Compounds II are then treated in accordance with the procedures set forth hereinabove in the treatment of Compounds L and M to yield the corresponding B-keto-A- norandrostanes (Compounds KK) which are also new compounds of this invention.

In order to obtain the saturated final products of this alternate procedure (Compounds LL) Compounds KK are treated in exactly the same manner as set forth hereinbefore in the treatment of Compounds N through P to obtain Compounds Q. Thus, Compounds KK (R H) are treated with an acid halide, converted into the diazoketones as with ethereal diazomethane and then reduced to yield the 3,ZO-diketo-A-nor-pregnanes (Compounds LL) which are new compounds of this invention.

Compounds KK may also be treated in accordance with the procedures set forth hereinabove in the treatment of compounds N through BB and EE to yield the saturated A-nor-A -pregnene-3,ZO-diones (Compounds MM) and the A-nor-A -pregnene-3,20-diones (Compounds NN), both of which are new final products of this invention.

Still more new final products of this invention may be obtained by the further processing of some of the derivative material obtained in the treatment of the original triterpenoid acid starting material. The additional processing required to obtain these new final products is set forth in the following equations wherein R, R and Z are as hereinbefore defined:

3 Org PP LXXXVII. R=CH C O; R':CH

coon =0 RR ss X0. n =on xon. Z=halide XCI. n'=n XCIII. z=onaooo XCIV. z=on XCV. z=n

onzz omz o=o CIVv Z halide (Cl, Dr, F, I)

CV. ZCH COO CVI. Z Ol-I C H'zZ YY UU CXII. Z=halide (Cl, Br, 15, I) C. Z=halide (Cl, Br, F. I) CXIII. Z=CH COO CI. Z=CH COO CXIV. Z OH CII. Z=OH CXV. Z=H CHI. Z=H

onl

CXVI. Z=halide CXVII. Z=CH COO oXX. Z==halide In the first step of this alternate process, Compounds L, (wherein R is CH CO and R is CH are reduced as by treatment with lithium borohydride to yield the 3'-acetoxy ll-hydroxy androstanes (Compounds 00) which are new products of this'invention. Compounds, 00 may then be further treated with a base, such as pyridine, and methanesulfonyl chloride in dimethylformamide to yield the A -andros'te'ne 17,8 carboxyl'ates (Compounds PP), which are also new compounds'of this invention.

Compounds 00 and PP may then be treated in accordance with the procedures set forth hereinabove in the production of Compounds N from Compounds L and M to yield the corresponding'A-nor-A -androstenes (Compounds RR) and 1'1,8-hydroxy-A-norandrostanes (Compounds QQ) which are also new compounds of this invention.

Compounds RR and QQ are then treated in the same manner as set forth hereinabove to yield Compounds Q, S and FF, thus producing respectively, the A-nor-A pregnen'es (Compounds WW), the A-nor-A -preg'nadienes (Compounds YY), the A-n'or-A -pregnadienes (Compounds ZZ) and the A-nor-A l pregnatrienes (Compounds AAA) from Compounds RR; and the 11,8- hydroxy-A-nor-pregnanes (Compounds SS), the llfi-hydroxy-A-nor-A -pregnenes (Compounds'TI), the llfi-hydroiiy-A-nor-A -p'r'egnenes (Compounds UU)'and the 115- 14 hydroxy-A-nor-A -pregnadienes (Compounds VV) from Compounds QQ. All these compounds are new final prodnets of the instant invention.

In addition to the foregoing, new compounds of this invention may be produced by an alternate procedure. The starting material employed in this alternate process is derived from the treatment of the original t'riterpenoid acid starting material-as described hereinbefore. This alternate process may be represented by the followinge'quations wherein R, R and Z are as hereinbefore defined:

CXXX. Z==halide C HyZ In the first step of this alternate process the A-nor- A androstene 175 carboxylates (Compounds V) are ketalized as by treatment with ethylene glycol in an acid medium at elevated temperatures to yield a mixture of the 3-a1kylenedioxy-A-nor-A -androstenes 17 3-carboxy1- ates (Compounds BBB) and the 3-alkylenedioxy-A-nor- A androstene 17,3 carboxylates (Compounds CCC), which are new compounds of this invention.

The mixture thus obtained may be separated into the individual compounds as by fractional crystallization or chromatographic separation. The 17fi-carboxylates (Compounds BBB and CCC) may be converted into the corresponding free acid compounds (wherein R is H) by treating the 17 8-carboxylates with a base, such as potassium hydroxide, in an alcohol medium thus producing the corresponding A-nor-M-androstene 175 carboxylic acids (Compounds BBB) and the A-nor-a -androstene- 17fl-carboxylic acids (Compounds CCC).

Compounds CCC may then be hydrolyzed by treatment with a mineral acid to yield the free acid of Compounds V. Compounds BBB may be treated with an organic acid, for example acetic acid at room temperature to yield the A-nor-A -androstene-lll-diones (Compounds DDD) which are new compounds of this invention. Compounds DDD may then be treated in accordance with the procedures described in the treatment of Compounds N, O and P, in order to yield the final products of this invention, Compounds S. Thus, Compounds DDD are treated with an acid halide to yield Compounds EEE, which are then methylated as with ethereal diazomethane to form Compounds FFF which are then reacted with the appropriate acid to yield the final products of this invention, Compounds S.

Still further processing of some of the derivatives of this invention is possible within the scope thereof. This additional processing may be represented by the following equations, wherein R, R and Z are as hereinbefore defined:

COOR

GGG

HHH

JJJ' CXXXV. Z=halide HO CXXXVI. Z=halidc; H ,:0:

KKK LLL OXXXVII. Z=halide oxxxvnr.

CXXXIX. 28:0:

CHN: C H2Z =0 (:J=O

MMM TT ornz 6:0

In the first step of this additional processing Compounds BBB are reduced as by treatment with lithium borohydride, to yield the 3-alkylenedioxy-A-nor-A -androstene-llfl-ols (Compounds GGG), which are new compounds of this invention. Compounds GGG may then be treated with a base, such as pyridine, and methanesulfonyl chloride in dimethylformamide to yield the A-nor- A landrostadienes (Compounds HHH) which are also new compounds of this invention.

Compounds GGG and HHH may then be processed in the same manner to yield the final products of this invention, Compounds TT and Compounds ZZ, respectively. Thus, treatment with an acid halide, e.g., oxalyl chloride yields the corresponding acid chlorides, Compounds 1]] and Compounds KKK; reaction thereof with a methylating agent, e.g., ethereal diazomethane, yields Compounds LLL and MMM, and the reaction of these compounds as set forth hereinabove in the treatment of Compounds BB, yields the final products of this invention, Compounds TT and ZZ, respectively.

Alternatively, Compounds GGG and HHH may be hydrolyzed with a fatty acid, such as acetic acid, to yield the A -3-keto-A-nor-androstenes (Compounds NNN) and the A6301) 3 keto-A-nor-androstadienes (Compounds OOO). Compounds NNN and Compounds 000 may then be treated with a mineral acid to yield respectively the A -3-keto-A-nor-androstenes (Compounds PPP) and the A 3 keto-A-nor-androstadienes (Compounds QQQ), all of which are new compounds of this invention. Compounds PPP and QQQ may then be treated in acco dance With the procedure hereinbefore described COOR COOR

COOR

RRR

COOR 000R! l /i l O 4 O l O O TTI SSS GLII. RCH CL. R=CH CLIII. R=H CLI. R=H

COZ COZ VVV CLV. Z=halide er 2:? l l r l i [3 Q [Z H e: e: v m l The first step of this alternate process involves ketalizing Compounds N by treatment with ethylene glycol in an acid medium at elevated temperatures to yield the 3 alkylenedioxy-A-norandrostanes (Compounds RRR) which are new compounds of this invention. Compounds RRR are then reduced as by treatment with lithium borohydride to yield the 3-alkylenedioxy-llB-hydoxy-A-norandrostanes (Compounds SSS), Which are also new compounds of this invention. Compounds SSS may then be treated with a base, such as pyridine, and methanesulfonyl chloride, in dimethylformamide to yield the A-nor-A androstenes (Compounds TTT), which are also new compounds of this invention. Compounds 'ITT and SSS may then be treated in the same manner to yield the final products of this invention Compounds WW and SS, respectively. Thus, treatment of the compounds with an 19 acid halide, e.g., oxalyl chloride yields the corresponding acid chlorides, Compounds VVV and UUU; reaction thereof with a methylating agent, e.g., ethereal diazomethane, yields Compounds XXX and WWW; and the treatment of these compounds as set forth hereinabove in the treatment of Compounds BB, yields the final products of this invention, Compounds WW and SS respectively.

In all the alternate process of this invention wherein the intermediate compounds employed in the production of the final products, possess a double bond in the six position it has been found that the final products will always possess a double bond in the five position. This shift in the bond position occurs whenever a mineral acid is employed in the process. To date it has not been found possible in the practice of this invention to obtain the final products of the invention possessing a double bond in the six position.

The following examples illustrate the invention (all temperatures being in Centigrade):

EXAMPLE 1 Eburicoic acid 3-pr0pi0nate (II) To a solution of 10 g. of eburicoic acid in 50 ml. of anhydrous pyridine is added 10 ml. of propionic anhydride and the mixture is allowed to remain at room temperature for 18 hours. Five grams of ice is then added and 30 minutes later the mixture is diluted slowly with 250 ml. of ice and water. The resulting precipitate is filtered, washed thoroughly with water, dried in vacuo and recrystallized from 95% alcohol yielding pure eburicoic acid 3-propionate (II).

Similarly, by substituting other acid anhydrides of acyl halides for the propionic anhydride in the procedure of Example 1, the corresponding 3-esters are formed. Thus, butyric anhyride and benzoyl chloride yield the 3-butyrate and 3-benzoate of eburicoic acid, respectively.

EXAMPLE 2 3,8-acetoxy-24-ket0-A Janostene-Z1-0ic acid (IV) Through a solution of 15 g. of eburicoic acid 3-acetate (I) in a mixture of 150 ml. of chloroform and 150 ml. of ethyl acetate, cooled in a Dry Ice-acetone bath, is passed 26.2 1. of ozone (1 mole of ozone contained in .89 l. of oxygen). The resulting solution is allowed to warm to room temperature and then added to a suspension of 975 mg. of pre-reduced 5% palladium on charcoal catalyst in 50 ml. of ethyl acetate. 550 ml. of hydrogen is taken up rapidly, following which the solution is filtered and the filtrate evaporated to dryness in vacuo.

Alternately the ozonide can be decomposed with zinc in acetic acid as follows: The ozonolysis mixture obtained from 50 g. of eburicoic acid S-acetate in 50 ml. of chloroform and 500 ml. of ethyl acetate, is allowed to warm up to when it is diluted with 50 ml. of glacial acetic acid. Powdered zinc is then added in portions with stirring and the temperature allowed to rise to A total of g. of zinc is required. After 2 /2 hours the reaction mixture is filtered and the zinc and zinc salts washed thoroughly with ethyl acetate. The ethyl acetatechloroform filtrate is washed thoroughly with water, dried over sodium sulfate and evaporated to dryness in vacuo. A total of about 56 g. of the crude keto acid IV is obtained.

The acid (IV) is obtained in pure form by chromatography on neutral alumina. For this purpose a solution of 14 g. of the crude acid is dissolved in 50 ml. of benzene and charged to the column containing 280 g. of alumina. 50% chloroformbenzene (9 l.) elutes about 1.9 g. of pure acid melting at about 234236, which is followed by about 1.2 g. of acid when the eluant is changed to 75% chloroform in benzene (3 1.). An additional 1.3 g. of pure acid is obtained with chloroform (5 1.). The column is then stripped with 5% acetic acid in chloroform (2. l.) which elutes about 10.4 g. of crude material which max.

Analysis.Calcd. for C H O (514.72): C, 74.67; H, 9.79. Found: C, 7.64; H, 9.54.

EXAMPLE 3 3 ,B-ace'toxy-Z4,28-dihydroxy-A -eburicene-21 -0ic acid (III) To a solution of 2 g. of eburicoic acid B-acetate (I) in 20 ml. of benzene and 2 ml. of pyridine is added dropwise a solution of 1 g. of osmium tetroxide in 10 ml. of benzene. Addition is complete in 1 hour and the reaction mixture is allowed to remain at room temperature for an additional 4 hours. The resulting dark solution is diluted with 76 ml. of dioxane and saturated with hydrogen sulfide for 15 minutes. The resulting suspension is filtered with the aid of Celite and the filtrate evaporated to dryness. The resulting residue (about 2:1 g.) is triturated with acetone leaving about 1.5 g. of the dihydroxy acid (III) melting at about 238242. Recrystallization of this material from ethanol furnishes the pure dihydroxy acid possessing the following properties: M.P. about 246284;

A221 2.95, 5.80, 6.05 and 8.00-8.10n

Analysis.-Calcd. for C H O C, 72.49; H, 9.92. Found: C, 71.76; H, 9.92.

EXAMPLE 4 3,9-acet0xy-24-ket0-A -lanostene-21-oic acid (IV) A solution of 1.17 g. of the 24,28-dihydroxy acid (III) in 200 ml. of .0108 molar lead tetraacetate solution in glacial acetic acid is allowed to stand at room temperature for 35 minutes. A few drops of ethylene glycol are then added to reduce the excess lead tetraacetate and the solution is concentrated in vacuo and diluted with water. The resulting suspension is extracted with ethyl acetate and the ethyl acetate extract washed several times with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crude produce (about 1.07 g.) on recrystallization from acetone furnishes about 700 mg. of the pure keto acid IV possessing the following properties: M.P. about 225-227"; [04] +50 (c., .43 in chlf.).

Analysis.-Calcd. for C H O C, 74.67; H, 9.79. Found: C, 74.32; H, 9.50.

This acid is identical in all respects with the product obtained in Example 2.

EXAMPLE 5 3fl-acetoxy-24-hydroxy-A -lanostadiene-Z]-0ic acid lactone (a-lactone) (V) and 3 3-acetoxy-24-hydroxy-A lanostadiene-Zl-oic acid lactone (fl-lactone) (VI) To a solution of 15.4 g. of 3B-acetoxy-24-keto-A -lanostene-21-oic acid (IV) in ml. of acetic anhydride is added 3.75 g. of anhydrous sodium acetate and the resulting suspension is heated under reflux for 10 hours. Upon cooling, the acetic anhydride solution is decanted from the sodium acetate and the latter washed thoroughly with benzene. The combined acetic anhydride-benzene solutions are evaporated to dryness in vacuo, the residue redissolved in benzene and filtered from the precipitated sodium acetate. The clear benzene solution is evaporated to dryness leaving a mixture of the uand fi-enol lactones (V and VI) (about 15.1 g.). Separation is achieved by chromatography on neutral alumina as follows: The total residue is dissolved in 50 ml. of benzene and 50 ml. of hexane and charged to a column containing 300 g. of

21 neutral alumina. Elution with 250 ml. of benzene-hexane (1:1) produces about 3.1 g. of crude crystalline 3,8-acetoxy-Z4-hydroxy-A -lanostadiene-2l-oic acid is lactone (oz-lactone) (V), which after crystallization from 95% ethanol is analytically pure and has the following properties: M.P. about 169-171"; +37";

max.

The 12.05 and 1263a band are diagnostic for the oclactone and are absent in the ,B-lactone.

Analysis.Calcd. for C H O (496): C, 77.37; H, 9.73. Found: C, 77,41; H, 9.82.

Continued elution of the alumina column with benzene (8 1.) produces a total of about 4 g. of material in 12 fractions, all of which melt between 150-160 and represent a mixture of the aand B-lactones. Rechromatography of this mixture is necessary to obtain the pure lactone. For the purpose all of the fractions are combined (4 g.), dissolved in 20 ml. of benzene and 80 ml. of hexane and charged to a column of 120 g. of neutral alumina. Elution with benzene-hexane (1:4) produces, in the first 500 1111., about 827 mg. of the pure a-lactone (V) which is followed by elution with the same solvent mixture (5.5 l.) and on clution with benzene-hexane (1:1, 2 l.) by a total of about 2.9 g. of material, representing a mixture of aand fl-lactone melting at about 158160. Continued elution of the column with benzene (9 1.) yields a total of about 1.2 g. of material which after recrystallization ethanol constitutes pure 3B acetoxy 24- hydroxy-n -lanostadiene 21 oic acid lactone (fi-lactone) (VI) (about 404 mg.) possessing the following properties: M.P. about 190191; [ab +64 (0., .87 in chif.);

A 5.70, 5.79, 5.97 (Weak), 8.08, 11.50, 11.50, 11.80,

EXAMPLE 6 3fl-acet0xy-24-hydr0xyA -lanstatriene-21 -0ic acid lactone (a-pyrone) (VII) A suspension of 180 mg. of palladium on charcoal in 25 ml. of p-cymene is distilled until approximately 3 ml. of solvent have been removed. The final temperature of the vapors is over 170. 250 mg. of the thoroughly dried a-enol lactone (V) is then added and the resulting suspension heated under reflux with stirring for 2 hours under a blanket of nitrogen. The mixture is cooled, filtered and the solvent removed in vacuo. The residual crystalline material on recrystallization from absolute ethanol furnishes the pure a-pyrone (VI) in about 75% yield possessing the following properties: M.P. about 228228.5; [M 114 (chlf.);

A233; 305 m (e=8,850); A213? 5.79, 5.90, 6.11, 6.35, 8.95, 11.90 and 12.69;;

Analysis.-Calcd. for C I-1 0 (494.68): C, 77.69; H, 9.37. Found: C, 77.77; H, 9.43.

When the fi-enol lactone (VI) is substituted for the oclactone (V) in Example 6 and the reaction time is prolonged to 6 hours, the pyrone (VII) is obtained in about 60% yield. Moreover, when a mixture of aand B-enol lactones (V and VI) (80 g.) is dehydrogenated with 80 g. of 10% palladium on charcoal in 700 ml. of pcymene for 6 hours, about 50 g. of the pure a-pyrone (VII) of M.P. about 226-228 is obtained.

Furthermore, if another ester of eburicoic acid, such as the 3-propionate (II), the 3-butyrate or the 3-benzoate is substituted for the 3-acetate in the procedures of either Example 2 or Example 3 and the procedures of Examples 2 through 6 are carried out, the corresponding 3-esters are obtained.

22 EXAMPLE 7 3,8,24-dihydr0xy-A -lan0statriene-2I -0ic acid lactone (VH1) To a solution of 510 mg. of potassium hydroxide in 10 ml. of ethylene glycol is added 73 mg. of the finely ground a-pyrone acetate (VII). The suspension is stirred and immersed in an oil bath held at a temperature of 150. After 5 minutes there results a clear pale yellow solution which is heated for an additional 4 minutes and then cooled. 25 ml. of water is added and the mixture extracted with ether. The ether extract is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. About 60 mg. of crystalline residue is obtained which on recrystallization from acetone furnishes long needles of the a-pyrone 3-01 (VIII) possessing the following properties: M.P. about 254-255;

A333, 303 m (e=9,000); 6.33, 11.85 and 12.62

Arzalysis.-Calcd. for C T-1 0 (452.65): C, 79.60; H, 9.80. Found: C, 79.50; H, 9.83.

EXAMPLE 8 24-hydroxy-B-keto-A -lan0statriene-21-0ic acid lactone To a solution of 95 mg. of 3/3-24-dihydroxy-A lanostadiene-Zl-oic acid lactone (VIII) in 3 m1. of acetone is added 1 mi. of a aqueous acetone solution of 20 mg. of chromium trioxide and 32 mg. of concentrated sulfuric acid. After 10 minutes methanol is added to reduce excess chromium trioxide and the solution is diluted with water and extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue on recrystailization from acetonitrile produces the analytically pure 3-ketone possessing the following properties: M.P. about 230-232;

222 5.87, 6.08, 6.30, 12.02 and 12.63,.

Analysis.Calcd. for C H O (415.63): C, 79.95; H, 9.39. Found: C, 80.21; H, 9.54.

EXAMPLE 9 3B-acetoxy-24-hydroxy-A' -lan0statriene-21-0ic acid lactone (IX) A solution of 5 g. of 3fi-acetoxy-24-hydroxy-A lanostatriene-Zl-oic acid lactone (VII) in 350 ml. of glacial acetic acid is saturated with dry hydrogen chloride gas first at 10 and finally as more HCl dissolves at 0. This requires a total of 30 minutes. The solution is maintained for an additional hour at 0 and then evaporated to dryness in vacuo. The resulting crystalline residue on recrystallization from ethanol and chloroform furnishes about 3.75 g. (75%) of a mixture consisting largely of the A and some of the A -isomer, M.P. 229-231"; 135 (chlf.). A sample of this product is chromatographed on acid-Washed alumina using a :1 ratio of alumina :to sample. After elution of the A -isomer with chloroform-benzene (1:8) the main fraction is eluted with pure chloroform -to give the pure A -isomer (IX), which on recrystallization from methanol has the following properties: M.P. 230230.5; [04 --144 (chlf.).

Analysis.-Calcd. for C H 0 (494.68): C, 77.69; H, 9.37. Found: C, 77.92; H, 9.40.

max.

Nuiol max.

essentially identical with the A -isomer VII except for the presence of a medium band at 12.05 1, which is Weak in the latter.

dried in vacuo to 40.

23 EXAMPLE 1o 3/3-hydr0xy-24-ket0-A' -lanstatriene-21-0ic acid lactone (X) Following the procedure of Example 9 but substituting g. of 3/8-hydroxy-24drew-A -lanostatriene-2l-oic acid lactone (VIII) for the acetate (VII), 3B-hydroxy- 24-keto-A -lanostatriene-2l-oic acid lactone (X) is obtained.

EXAMPLE l1 3,8-acet0xy4,4,14-trimethyl-A -5a-andr0stene-7,1 1 dione-I 7fl-carb0xylic acid (XI) To a solution of 50 g. of 3,8-acetoxy-24-hydroxy- 21 -lanostatriene-2l-oic acid 21,24-lactone (VII) in 3 l. of acetone maintained at a temperature of 33-37 is added with stirring a total of 120 g. of finely pulverized potassium permanganate. The potassium permanganate is added in 20 g. portions, first more rapidly, later on at greater intervals so as to maintain the proper temperature and making sure that the permanganate color is discharged prior to new additions. The total time of addition is about 1 hour and 20 minutes and the reaction is allowed to proceed until all the permanganate color is discharged (approximately an additional 1 to 1 /2 hours). Upon completion of the oxidation 60 ml. of Water is added, the mixture cooled to 0 in an ice-bath and sulfur dioxide is passed through the solution until all the manganese dioxide has been transformed into colorless manganous sulfate. The suspension is filtered and the filter cake washed thoroughly with hot acetone. The yellow acetone solution is concentrated in vacuo to 800 ml. and

the 3/8-acetoxy-4,4,14-trimethyl-A -5ot-androstene-7,l1di

one-17fl-carboxylic acid (XI) precipitated by the addition with stirring of 2 l. of ice and water. The precipitated acid (XI) is filtered off, Washed with water and The dried material (30.8 g.) is dissolved in 200 ml. of hot absolute alcohol and allowed to crystallize. 2.3 g. of lactone starting material (VII) separates and the resulting mother liquor is taken to dryness. The residue is then dissolved in 75 ml. of acetonitrile and the acid (XI) allowed to crystallize. The first crop of 12.3 g. of 3fi-acetoxy-4,4,14-trimethy1-A -5otandrostene-7,1l-dione-l7l3-carboxylic acid (XI) melts at 245-248, the second crop of 1.61 g. of 3,B-acetoxy-4,4, 14 trimethyl-A -Su-androstene-7,1l-dione-llB-carboxyfic acid (XI) melts at 242245 and the third crop of 2.17 g. of 3B-acetoxy-4,4,14-trimethyl-A -5u-androstene-7,1ldione-l7fi-carboxylic acid (XI) melts at 235-238". The analytically pure 3B-acetoxy-4,4,14-trimethyl-A '5a-androstene-7,l1-dione-17fi-carboxylic acid (XI) obtained by recrystallization from methanol has the following properties: M.P. 252-255-, [011 +85 (c., 1.24 in chlf.);

1;}; 268 m (e=9,100) 12:22 5.82, 5.94, 6.06 and 7.93,.-

Analysis (after drying at 135).-Calcd. for

c H .,o /2H,o 7 (439.53); c, 6831,11, 8.02. Found: 0, 68.51; H, 7.95.

EXAMPLE 12 3,8-acet0xy-4,4,14-trimethyl-A 5a-androstene-Z11 dione-J 7fl-carb0xylic acid (XI) Following the procedure set forth in Example 11 but substituting 50 g. of 3B-acetoxy-24-hydroxy-A' lanostatriene-Zl-oic acid 21,24-lactone (IX) for 3fl-acetoxy 24 hydroxy-A -lanostatriene 21 oic acid 2l,24-lactone, yields 3;? acetoxy-4,4,l4-trimethyl-A 5aandrostene-7,1l-dione-lldcarboxylic acid (XI).

241 EXAMPLE 13 Methyl 3,8-acetoxy-4,4,14-trimethyl-A -5 ot-androstene- 7,1 1 -diorze-1 7 fl-carboxylate (XII) To a suspension of 12.5 g. of 35-acetoxy-4,4,146t-trimethyl-A 6a-androstene-7,11 dione-17,8 carboxylic acid (XI) in 250 ml. of methanol is added at 0 a solution of diazornethane in ether until all the acid dissolves and there is no longer an evolution of nitrogen. Upon com pletion of the reaction the ether is removed in vacuo and the solution concentrated to a total volume of about ml. The methyl 3fl-acetoxy 4,4,14 trimethyl-A -5a-androstene-7,11-dione-l7l3-carboxylate (XII) readily crystallizes yielding 9.2 g. of material (MP. -172") in the first crop and an additional 2 g. (M.P. 158-160) in the second crop. The analytical sample, recrystallized from methanol, has the following properties: M.P. 178- 179"; [M +88 (c., 1.18 in chlf.);

N22,, 268 my. (e=9,400); A232 5.73, 5.80 and 5.94;

Analysis.-Calcd. for C H O (444.55): C, 70.24; H, 8.16; OCH 6.98. Found: C, 70.36; H, 8.11; OCT-l 6.89.

EXAMPLE 14 M etlz yl 3,Bacct0xy-4,4,I 4-trimethy l-5 ot-androstane- 7,1 1-di0ne-17fi-carb0aylate (XV) To a refluxing solution of 17 g. of methyl 35-acetoxy- 4,4,146t trimethyl-A da-androstene-7,11-dione-17fi-carboxylate (XII) in 425 ml. of glacial acetic acid is added, over a 20 minute period, 170 g. of 20 mesh granular zinc. The yellow color lightens and complete decolorization is achieved by the portionwise addition of a total of 3 g. of zinc dust. Total reaction time is 2 hours. The solution is cooled and filtered, the zinc washed with chloroform and the solvents concentrated to small volume in vacuo. The residue is distributed between water and chloroform, the chloroform solution Washed with dilute sodium bicarbonate, dried over sodium sulfate and concentrated to a small volume. Upon addition of methanol the very insoluble methyl 3fl-acetoxy-4,4,l4- trimethyl-Sot-androstane-7,1l-dione-17fl-carboxylate (XV) crystallizes rapidly, yielding a first crop of 12.5 of (XV) having an M.P. of 258260 and a second crop of 2.7 g. of (XV) having an M.P. of 235-240". The analytically pure compound is obtained by recrystallization from chloroform-methanol or acetonitrile and has the following properties: M.P. 262";

A315; no absorption at 268 m k211i? 8.37 [a] +70 (c., 1.06 in chlf.)

Analysis.Calcd. for (3 1-1 0 (446.56): C, 69.93; H, 8.58. Found: C, 70.07; H, 8.38.

EXAMPLE 15 Methyl 3f3-acet0xy-7-ethylenedithi04,4,14-trimethyl- 5 ot-andr0stane-1 1 -0ne-1 7,8-carb0xylate (XVIII) To a mixture of 58 ml. of ethanedithiol and 47 ml. of twice distilled boron trifluoride etherate is added 14 g. of methyl 3fl-acetoxy-4,4,14-trimethyl-5:x-androstane-7, 1l-dione-17B-carboxylate (XV). All the material dissolves within 1.5 hours and after a total reaction time of 23 hours at room terneprature, 290 ml. of cold methanol is added. The mixture is chilled in an ice-bath for 1 hour and filtered. The crystals are washed thoroughly with cold methanol and dried in a vacuum oven at 40. 12.5 g. of methyl 3fi-acetoxy-7-ethylenedithio-4,4, 14 trimethyl 50c androstane-l1-one-l7B-carboxylate (XVIII) melting at 210211 is obtained. The analytical sample, recrystallized from methanol and chloroform, has the following properties: MP. 211-212"; [a] +19 (c., .60 in chlf.);

Al1(1l )'SlS.-Cfll0(l. for 0 14 0 54 522.73 c, 64.32; H, 8.09; s, 12.27. FOllI'lClI c, 64.12; H, 8.11; s, 12.14.

5.73, 5.85, 8.00 and 25 EXAMPLE 16 To a solution of 12.3 g. of methyl 3,8-acetoxy-7-ethylene-dithio 4,4,14 trimethyl-5a-androstane-1Lone-1713- carboxylate (XVIII) in 1.2 1. of absolute ethanol is added 414 ml. of commercial Raney nickel, from which all water had been removed by repeated washing with absolute ethanol. The resulting suspension is refluxed for 18 hours, the reaction mixture filtered While hot and the Raney nickel cake washed with large volumes of hot ethanol taking care to keep the pyrophoric catalyst covered with solvent at all times. The filtrate and washings are concentrated until crystals appear. These crystals are filtered after cooling yielding a first crop of 8.5 g. of (XIX) melting at 218-220 and a second crop of 508 mg. of (XIX) melting at 217-218". The anatlytically pure material obtained by recrystallization from methanol has the following properties: M.P. 219-220";

5.78, 5.82, 8.01 and 8.36 11; [a] +6S (c., .61 in XNuioI max.

chlf

Analysis.Calcd. for C H O (431.58): C, 71.19; H, 9.32. Found: C, 72.54; H, 9.39.

EXAMPLE 17 4,4,14-trimethyl-5a-rmdrostane-jfl-ol-l Z -01ze-1 7 -carboxylic acid (XX) A solution of 4 g. of methyl 3,8-acetoxy-4,4,14-trimethyl-Sa-andrOstane-I1-on -17fl-carboxylate (XIX) in 600 ml. of 5% methanolic KOH (.73 N) and 40 ml. of Water is refluxed under nitrogen for 7% hours. The solution is acidified with glacial acetic acid and the resulting solution concentrated in vacuo. Water is added and after coling the resulting crystals removed by filtration. After drying, 3.45 g. of the acid (XX), melting at 310, is obtained. The analytically pure material, crystallized from chloroform-methanol, has the following properties: M.P. 335-345; [(1.1 +49 (c., .47 in methanol);

A 2.84, 5.77 and 5.92

A1mlysz's.Calcd. for C H O (376.52): C, 73.36; H, 9.64. Found: C, 73.43; H, 9.40.

EXAMPLE 18 4,4,14-trimethyl-A -5a-andr0stezze-3/3-ol-7J 1 -dine-1 75- carboxylic acid (XIII) EXAMPLE 19 4,4,14-trimethyl-a-androstane-3fi-ol-7J 1 -di0ne-1 75- carboxylic acid (WI) Following the procedure set forth in Example 17 but substituting methyl-3,8-acetoxy-4,4,14-trimethyl-5a-androstane-7,1l-dione-17B-carboxylate (XV) for methyl-3B- acetoxy 4,4,14-trimethyl-5u-androstane-11-one-17fi-carboxylate (XIX), yields 4,4,14-trimethyl-5a-androstane-3fiol-7,ll-dione-l7 3-carboxylic acid (XVI).

2% EXAMPLE 2O Methyl-4,4,14-trimethyl-5a-aizdrostanedfi-ol- 11-0ne-J 7 fi-carboxy late (XXI) To a suspension of 2 g. of 4,4,14-trimethyl-5a-androstane-35-ol-11-one-17fl-carboxylic acid (XX) in 40 ml. of methanol is added, at 0, an excess of diazomethane in ether. After 20 minutes the excess diazomethane is removed by the addition of glacial acetic acid and the ether-methanol solution concentrated in vacuo. From the concentrated methanolic solution 1.9 g. of methyl- 4,4,14 trimethyl 5a androstane 35 o1 11-one-17fi- 'carboxylate (XXI) is readily crystallized having an M.P. 0g 238-239". Analytically pure material is obtained by recrystallization from methanol and possesses the following properties: M.P. 240-241"; [04] +60 (c., 1.08 in chlf.);

Analysis.-Calcd. for C d-1 0 (390): C, 73.80; H, 9.81. Found: C, 73.81; H, 9.61.

EXAMPLE 21 M ethyl-4,4,1 4-trimethy l-A -5 a-an drostene-S 8- 01-7,]1 -di0ne-1 7,8-carb0xy late (XIV) Following the procedure set forth in Example 20, but substituting 4,4,14-trimethyl-A -5a-androstene-3B-ol-7,11- dione-17B-carboxylic acid (XIII) for 4,4,14-trimethy1-5aandrostane-3B-ol-11-one-17 3-carboxylic acid (XX), yields methyl 4,4,14 trimethyl A 50c androstene 35 ol- 7, 11-dione-17fl-carboxylate (XIV).

EXAMPLE 22 Methyl-4,4,14-trimethyl-5a-andr0stane-3B-0l- 7,11 -di0n.e-1 7,8-carb0xy late (XVII) Following the procedure set forth in Example 20, but substituting 4,4,14-trimethyl-5a-androstane-3fi-ol-7,1l-dione-17B-carboxylic acid (XVI) for 4,4,14-trimethyl-5uandrostane-3/8-ol-11-one-17B-carboxylic acid (XX) yields methyl 4,4,14 trimethyl 5oz androstane 3 8 ol- 7,11-dione-17 3-carboxylate (XVII).

EXAMPLE 23 Methyl 4,4,14-trimethyl-3B-acetoxy-5a-androstane- .I 1fi-0l-17fi-carb0xylate (LXXXVI) A solution of 500 mg. of methyl 4,4,14-trimethyl-3fiacetoxy-5oa-androstaued1,8-ol-17B-carboxylate (XIX) and 500 mg. of lithium borohydride in 50 ml. of freshly distilled tetrahydrofuran is stirred at room temperature for 2 hours. Excess lithium borohydride is then destroyed with 10% aqueous acetic acid, the mixture diluted with water and chloroform and the chloroform extract washed with water, dilute bicarbonate and again with water. After drying over sodium sulfate the solvents are removed in vacuo and the resulting residue recrystallized from methanol. The analytical sample has the following properties: M.P. 219-220"; [a] +72 (c., 1.04 in chlf.);

2.81, 5.75, 5.81, 7.95 and 8.21;;

Analysis.-Calcd. for C H O (534.60): C, 71.85; H, 9.74. Found C, 71.94; H, 9.7 6.

EXAMPLE 24 Methyl 4,4,1 4-trim ethyl-3/3-acet0xy-A -5 ocandrostene-Z 7B-carb0xylate (LXXXVII) A solution of 250 mg. of methyl 4,4,l4-trimethyl-3B- acetoxy-Sa-androstane-l1fl-o1-17fi-carboxylate (XIX) in 10 ml. of dimethylformamide, 1 ml. of anhydrous pyridine and .5 ml. of methanesulfonyl chloride is allowed to remain at room temperature for 17 hours. Water is added to the mixture and, after cooling, the crystals are removed by filtration. The washed and dried crystals weigh 207 mg. and melt at 163-164". Recrystallization 27 of this material from methanol furnishes the analytically pure compound melting at 167; [(11 +95 (c., .5 in chlf.);

REE? 5.75, 8.02 and 8.36;:

Analysis.Calcd. for C H O (416.98): C, 74.96; H, 9.60. Found: C, 74.75; H, 9.82.

EXAMPLE 25 Methyl-4,4,14-trimethyl-3fl-acet0xy-5a-andl'ostane- 17B-carb0xylate (LXVI) A solution of 200 mg. of methyl-4,4,14-trimethyl-3B- acetoxy-5a-androstane-7,1 1-dione-17fl-carboxylate (XV) 200 mg. of hydrazine hydrate and 500 mg. of potassium hydroxide in 5 ml. of ethylene glycol is refluxed for 24 hours. The mixture is then cooled, diluted with water, acidified to pH 2 and the steroids extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and the solvent removed in vacuo. The resulting material is reacetylated with /2 cc. of acetic anhydride and /2 cc. of pyridine for 18 hours at room temperature and the resulting material remethylated with diazomethane. Removal of the solvent leaves the methyl 4,4,14 trimethyl 3;? acetoxy 5a androstane- 17fi-carboxylate as a crystalline solid.

Similarly, following the procedure set forth in Example 25, but substituting methyl-4,4,14-trimethyl-3fl acetoxy- 5a-androstane-11-one-l7fi-carboxylate (XIX) for methyl- 4,4,14 trimethyl-3fi-acetoxy-jia-androstane 7,11-dione- 17fi-carboxylate (XV), methyl-4,4,14-trimethyl-3B-acetoxy-5ot-androstane-l7fi-carboxylate (LXVI) is obtained.

EXAMPLE 26 Methyl 3-is0pr0pylidene-14-methyl-A-n0r-5a-andr0stane- 1 -ne-1 7,8-cm'b0xylate (XXII) To a solution of 1.2 g. of methyl 4,4,14-trimethyl-aandrostane-"a'fi-ol-l1-one-17fi-carboxylate (XXI) in 240 ml. of dry toluene maintained at 0 and protected from light, is added 1.2 g. of phosphorus pentachloride. Immediately after the addition of the latter a rapid stream of helium gas is passed through the suspension with stirring. After 20 minutes saturated sodium bicarbonate is added and the two layers mixed thoroughly until all the phosphorus oxychloride is hydrolyzed. The toluene solution is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue upon crystallization from methanol yields a first crop of 930 mg. of XXII, melting at ISO-151 and a second crop of 67 mg. of XXII, melting at 146149. The analytically pure material after recrystallization from methanol has the following properties: M.P. 150-15l; [0:1 :3 +63 (0., .59 in chlf.);

Analysis.-Calcd. for C H O (372.52)'. C, 77.37; H, 9.74. Found: C, 77.44; H, 9.51.

EXAMPLE 27 4,4,] 4 -trimetl1 yl-5 a-andrOStane-S 5,1 I fi-d i 0l- 17B-carb0xylic acid Following the procedure set forth in Example 17 but substituting methyl-4,4,l4-trirnethyl-3,B-acetoxy-Sa-androstane 11,6 ol 17;? carboxylate for methyl-3,8-acetoxy- 4,4,14 trimethyl 5a androstane-l l-one-l7l3-carboxylate (XIX). yields 4,4,14 trimethyl 5a androstane-3fi-l1fldiol-17fl-carboxylate acid.

EXAMPLE 28 Methyl 4,4,14-trimethyl-Swandrostarze-BBJ1(3- dz'0l-1 7fi-carb0xylate Following the procedure set forth in Example 20, but substituting 4,4,14 trimethyl-Sa-androstane-SB,1lB-diol- 17-fl-carboxylic acid for 4,4,l4trimethyl-h-androstane- 3,8-01-1l-one-17B-carboxylic acid (XX). yields methyl 28 4,4,14 trimethyl-Sot-androstane-3p,1lB-diol-17p-carboxylate.

EXAMPLE 29 4,4,14-trimethyl-A -5oz-andr0stene-3[3-0l- 1 7,8-carb0xylic acid Methyl 4,4,14trimethyl-A -5a-andr0stene- 3B-ol-1 7fi-carboxylate Following the procedure set forth in Example 20, but substituting 4,4,14 trimethyl-A -5a-androstene-3,B-ol- 17fi-carboxylic acid for 4,4,14-trimethyl-Sa-androstane- 35-01-1l-one-17fl-carboxylic acid (XX), yields methyl 4,4,14 trirnethyl-A -5a-androstene-3fi-ol-17fi-carboxylate.

EXAMPLE 31 4,4,14-trimethyI-Sa-aIzdrOstane-fiB-l 7-carb0xylic acid Following the procedure set forth in Example 17 but substituting methyl 4,4,l4-trimethyl-3B-acetoxy-5et-androstane 17B-carboxylate for methyl 3fi-acetoxy-4,4,l4-trimethyl 5a androstane-l1-one-17fi-carboxylate (XIX), yields 4,4,14 trimethyl 50c androstane 313 ol 17ft carboxylic acid.

EXAMPLE 32 Methyl 4,4,14-trimcthyl-5ot-andr0stane-3fi-0l- J 7/8-carb0xylate Following the procedure set forth in Example 20, but substituting 4,4,14-trimethyl-5a-androstane-iafi-ol-17;8-carboxylic acid for 4,4,14-trimethyl-5a-androstane-3fi-ol-l1- one-17,8-carboxylic acid (XX) yields methyl 4,4,14-trimethyl-5a-androstane-3fl-ol-17,3-carboxylate.

EXAMPLE 33 Methyl 3-is0pr0pylidenc-14-methy l-A-n0r-5otandrostalze-l Ifl-ol-I 7/i-carb0xylate Following the procedure set forth in Example 26 but substituting methyl 4,4,14-trimethyl-1a-androstane-3/3-1lfldiol-17B-carboxylate for methyl 4,4,14-trimethyl-5u-androstane 3 8 ol 11-one-17fi-carboxylate (XXI) yields methyl 3-isopropylidene-14-methyl-A-nor-5a-androstane- 1 1 8-ol-17p-carboxylate.

EXAMPLE 34 Methyl 3-is0pr0pylidene-14-methyl-A-n0r- A -5a-andr0stene-1 7,8-carboxylate Following the procedure set forth in Example 26 but substituting methyl 4,4,14-trimethyl-A -Sa-andmstene- 3/3-ol-17 3-carboxylate for methyl 4,4,l4-trimethy1-5uandrostane 3,8 ol-11-one-17fi-carboxylate (XXI) yields methyl 3-isopropylidene-14-methyl-A-nor-A -Soc-androstene-17fi-carboxylate.

EXAMPLE 35 Following the procedure set forth in Example 26, but substituting methyl 4,4,l4-trimethyl-5a-androstane-3fi-ol- 17B-carboxylate for methyl 4,4,14-trimethyl-5wandrostane-3fl-ol-1l-one-l7 8-carboxylate (XXI), yields methyl -3-isopropylidene 14 methyl-A-nor-Sa-anclrostane-lcarboxylate.

with glacial acetic acid and diluted with water.

2% EXAMPLE 36 E32 3.07, 5.77, 5.89 and 6.00

Analysis.-Calcd. for C H O (385.51): C, 77.05; H, 9.56. Found: C, 77.13; H, 9.67.

EXAMPLE 37 Following the procedure set forth in Example 36 but substituting methyl 3-isopropylidene-14-methyl-A-nor-5aandrostane-11B-ol-17fi-carboxylate for methyl 3-isopropylidene 14 methyl-A-nor-Su-androstane-1Lone-17,8- carboxylate (XXII), yields 3-isopropylidene-14-methyl- A-nor-Sa-andrOstane-I 1,8-01- 17B-carboxylic acid.

EXAMPLE 38 3-isopropylidene-14-m ethy l-A -nr-A -5aandrosten e-l 7fi-carb0xylic acid Following the procedure set forth in Example 36, but substituting methyl 3-isopropylidene-14-methyl A nor- A -5a-androstene-17B-carboxylate for methyl 3-isopropylidene 14 methyl-A-nor-h-androstane-1Lone-17ecarboxylate (X) yields 3-isopropylidene 14 methyl-A- mer-A -5a-androstene-17,3-carboxylic acid.

EXAMPLE 39 3-is0pr0pyIidene-1 4-methyl-A -n0r-5 lx-androstane- 17,6-carb0xylic acid Following the procedure set forth in Example 36, but substituting methyl 3-isopropylidene-14-methy1-A-11or-5aandrostane-l7fi-carboxylate for methyl 3-4isopropylidene- 14-methyl-A-nor-5rx-androstane 11 one 17B carboxylate (XXII) yields 3-isopropylidene-14-methyl-A-nor- 5a-androstane-17B-carboxylic acid.

EXAMPLE 40 M ethyl 14-methyl-A -nor-5a-andr0stane-3,1l dione-I 7, 3-carb0xylate (XXV) A solution of 1.5 g. of methyl 3-isopropylidene-14- methyl-A-nor-Su-androstane-1l-oue 17,6 carboxylate (XXII) in '80 ml. of ethyl acetate is ozonized at 20 until a potassium iodide trap, placed behind the reaction vessel, shows the color of iodine. This requires 3.6 liters of gas containing .714 mmole of ozone per liter. The calculated amount for 1 mole of ozone per mole of substrate is 3.2 liters. The ozonolysis solution is then allowed to Warm up to 0", 3.5 ml. of glacial acetic acid is added and the ozonide decomposed reductively by the portionwise addition of 12 g. of zinc dust. After stirring for a total of 1 hour at room temperature the ozonide is completely decomposed as indicated by a negative starch iodide test. The mixture is then filtered, the ethyl acetate filtrate extracted with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue upon recrystallization from acetone-hexane yields 590 mg. of the pure methyl 14-methyl-A-nor-5aandrostane-3,11-dione-17/3-cmboxylate (XXV), an additional 280 mg. of (XXV) melting at 176179, and a 39 third crop of 184 mg. of (XXV). The analytically pure methyl 14-methyl-A-nor-5u-androstane-3,1l-dione carboxylate (XXV), obtained by recrystallization from acetone-hexane has the following properties: MP. 178- 180"; on cooling the sample resolidifies and then remelts at 216-218". [11], +5.5 (c., .64 in chlf.);

Nai0l Analysis.Calcd. for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.75; H, 8.98.

EXAMPLE 41 Methyl 1 4-m ethyl-A -nor-5a-andr0stane-1'1 B- 0l-3-0ne-17B-carboxylate (LXXXVIII) Following the procedure set forth in Example 40, but substituting methyl 3-isopropylidene-14-methyl-A-nor-5a androstane-l1fl-ol-17B-carboxylate for methyl 3-isopropylidene 14 methyl-A-nor-Srx-androstane-l1-one-17ficarboxylate (XXII), yields methyl 14-methyl-A-nor-5aandrostane-l1fl-ol-3-one-17B carboxylate (LXXXVIII) EXAMPLE 42 M ethyl 14-methyl-A-nor-A -5a-androstene-3-one- 17fi-carb0xylate (XC) Following the procedure set forth in Example 40 but substituting methyl 3-isopropylidene-A-nor-A -Swandrostene-17,8-carboxylate for methyl 3-isopropylidene-14- methyl A nor 5a androstane 11 one 17p carboxylate (XXII), yields methyl 14-methyl-A-nor-A 5a-androstene-3-one-17,3-carboxylate (XC).

EXAMPLE 43 Methyl 14-methyl-A-n0r-5a-androstane-3-one-1 7 5- carboxylate (LXVII) Following the procedure set forth in Example 40 but substituting methyl 3-isopropylidene-A-nor-5a-androstane- 17/3-carboxylate for methyl 3-isopropylidene-14-methyl- A-nor-Sa-androstane 11 one 175 carboxylate (XXII) yields methyl 14-rnethyl-A-nor-5a-androstane-3one-17,8-

v carboxylate (LXVII).

EXAMPLE 44 Methyl 14-methyl-A-rz0r-5,B-andr0stane-3,11-di0ne- 1 7fi-carb0xylate (XXVI) k 5.74 and 5.86

max.

Analysis.-Calcd. for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.85; H, 8.78.

EXAMPLE 45 Methyl 14-m ethyl-A -n0r-5-a'ndr0stane-3,1 1 -di0ne- 1 7,6-carb0aylate (XXVI) A solution of 100 mg. of methyl 14-methyl-A-nor-5aandrostane-3,11-dione-17fl-carboxylate (XXV) in 5 ml. of 0.1% HBr in glacial acetic acid is allowed to remain at room temperature for 10 minutes. The solution is neutralized with aqueous bicarbonate, diluted with water, concentrated in vacuo and extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. The residue upon recrystallization from methanol furnishes methyl 14-methyl-A-n0r- 5fl-androstane-3,11-dione-17B-carboxylate (XXVI).

31 EXAMPLE 46 Methyl 14-methyl-A-n0r-55-andr0stane-1 I ,8-l-3-0ne- 1 7B-carb09tylate (LXXXVIII) Following the procedure set forth in Example 44, but substituting methyl l4-methyl-A-nor-5tat-androstane-115- ol-3-one-l7fi-carboxylate for methyl 14-methyl-A-nor-5aandrostane 3,11 dione 17/3 oarboxylate (XXV) yields methyl 14-methyl-A-nor-S S-androstane-1lB-ol-3-one-17/8- carboxylate (LXXXVIII).

EXAMPLE 47 Methyl 14-methyl-A-ri0r-A -5/3-andr0stene-3-0ne- 17/3-carboxylate (XC) Following the procedure set forth in Example 44, but substituting methyl 14-methyl-A-nor-A -Swandmstene- 3-one-17B-carboxylate for methyl 14-methyl-A-nor-5aandrostane 3,11 dione 17 3 carboxylate (XXV) yields methyl 14-methyl-A-nor-A -5fl-androstene-3-one-17;3-

. carboxylate.

EXAMPLE 48 Methyl 1 4-methyl-A-n0r-5 B-androslane-3-0ne-1 713- carbaxylate (LXVIII) Following the procedure set forth in Example 44, but substituting methyl 14-methyl-A nor-5ot-androstane-3-one- 17,8-carboxylate for methyl 14-methyl A-nor-5a-androstane-3,l1-dione-17B-carboxylate (XXV) yields methyl 14 methyl A nor 5e androstane 3 one 17 3- carboxylate (LXVIII).

EXAMPLE 49 14-methyl-A-n0r-5t3-andr0stane-3,1 1-dione-1 713- carboxylic acid (XXVII) To a mixture of .7 N KOH in methanol and 4.6 ml. of water, which has been refluxed for 10 minutes and cooled under a blanket of helium is added 460 mg. of methyl 14 methyl A nor 5a androstane 3,11 dione 17,6- carboxylate (XXV) and the resulting light yellow solution is refluxed for 7 /2 hours under a blanket of helium. The mixture is then cooled and after the addition of 5 ml. of glacial acetic acid is diluted with water. After removal of the bulk of the methanol in vacuo the 14-methyl-A- nor 5 3 androstane 3,11 dione 17 3 carboxylic acid (XXVII) crystallizes and is filtered and washed with water. The 14-methyl-A-nor-5fi-androstane-3,1l-dionel7 3-oarboxylic acid melts at 255263. The analytically pure 14-methyl-A-nor-5fi-androstane-3,1 1-dione-17B-carboxylic acid obtained after recrystallization from methanol and drying at 110 has the following properties: M.P. 270-272"; +184 (c., 1.04 in chlf.);

max.

Analysis.-Calcd. for C H O (332.42): C, 72.26; H, 8.49. Found: C, 72.22; H, 8.55.

EXAMPLE 50 1 4 -methyl-A -n0r-5 fi-androstane-3 ,1 1 -di0ne-] 7a carboxylic acid (XXVII) EXAMPLE 51 14-methyl-A-nor-5;3-arzdr0stane-11fi-0l-3-0ne-17f3- carboxylic acid (LXXXIX) Following the procedure set forth in Example 49 but substituting methyl 14-methyl-A-nor-5a-androstane11,8- ol-3-one-17fl-carboxyla-te for methyl 14-methyl-A-nor-5aandrostane-3,1l-dione-17p3-carboxylate (XXV) yields 14- 32 methyl-A-nor-Sfi-androstane-1lfi-ol-3-one-l7fl carboxylic acid (LXXXIX).

EXAMPLE 52 14-methy l-A mar-A -5/3-andr0ste1ze-3-0ne-1 7 pcarboxylic acid (XCI) Following the procedure set forth in Example 49 but substituting methyl 14-methyl-A-nor-A -5et-androstene- 3 one 17fi-carboxylate for methyl l4-methyl-A-nor-5aandrostane-3,11-dione-17fi-carboxylate (XXV) yields 14- methyl-A-nor-A -5a androstene-3-one-17 8-carboxylic acid (XCI) EXAMPLE 53 14-n zethyl-A -n0r-5;3-andr0stane-3-0ne-l 7ecarboxylic acid (LXIX) Methyl 14-methyl-3-acet0xy-A mar-A -andr0stene- 1l-0ne-17fl-carh0xylate (XLV) A solution of 30 mg. of methyl 14-methy1-A-nor-Saandrostane-3,11-dione-1718-carboxylate (XXV) and 40 mg. of p-toluenesulfonic acid in 5 ml. of redistilled isopropenyl acetate is slowly distilled under anhydrous conditions. One ml. is distiled otf rapidly and a second milliliter over a 30 minute period. After a total of 45 minutes the mixture is cooled to room temperature, taken up in chloroform and the chloroform extract washed with dilute sodium bicarbonate and water, dried over sodium sulfate and taken to dryness in vacuo. 42 mg. of crude residue melting at 163-165 is triturated with ether and the resulting crystals (18 mg.) recrystallized from methanol. The pure methyl 14-methyl-3-acetoxy-A-nor-A -androstene-l1-one-17t3-carboxylate (XLV) has the following properties: M.P. 170-171"; +124 (c., .38 in chlf.);

REE, 5.70, 5.77 and 5.88;;

Analysis.Calcd. for C H O (388.49): C, 71.10; H, 8.30. Found: C, 71.03; H, 8.37.

EXAMPLE 55 Methyl l4-methyl-3-acet0xy-A-n0r-A -andr0stene- 11/3-0l-1 7,8-carb0xylate Following the procedure set forth in Example 54 but substituting methyl 14-methyl-A-nor-5a-androstane-l1B- ol-3-one-17fi-carboxylate for methyl 14-methyl-A-nor-5aandrostane 3,11 dione-17B-carboxylate (XXV) yields methyl 14 methyl-3-acetoxy-A-nor-A -androstene-1113- ol-17,B-carboxylate.

EXAMPLE 56 Methyl 14-methyl-3-acet0xy-A-n0r-A -androstadiene-I 7fi-carboxylate Following the procedure set forth in Example 54 but substituting methyl 14-methyl-A-nor-A -5a-androstene 17,6-carboxylate for methyl 14-methyl-A-nor-5tx-androstane-3,11-dione-17fl-carboxylate (XXV), yields methyl 14 methyl-3-acetoxy-A-nor-A -androstadiene-lcarboxylate.

EXAMPLE 57 Methyl 14-methyl-3-acet0xy-A mar-A 4111 drostene- J 7,8-carb0xylate Following the procedure set forth in Example 54 but substituting methyl 14 methyl-A-nor-Set-androstane-17B- carboxylate for methyl 14-methyl-A-nor-Ste-androstane- 33 3,11 dione 17,8-carboxylate (XXV) yields methyl 14- methyl 3 acetoxy-A-nor-A -androstene-17,8-carboxylate.

EXAMPLE 58 Methyl 14-methyl-3-acezoxy-A -rzor-A -andrstene- 1.1 -on 6-1 7 fl-carboxylate (XLV) Following the procedure set forth in Example 54 but substituting methyl 14-methyl-A-nor-5/3-androstane-3,11- dione-17/3-carboxylate (XXVI) for methyl 14-methyl-A- nor-Sa-androstane 3,11 dione-17/3-carboxylate (XXV) yields methyl 14-methyl 3 acetoxy-A-nor-A -androstone-1l-one-l7fi-carboxylate (XLV) EXAMPLE 59 14-methyl-3-acet0xy-A mar-A -andr0steize-]l -one- 1 7 B-carhoxylic acid (XLVI) Following the procedure set forth in Example 54, but substituting 14 methyl-A-nor-S/3-androstane-3,1l-dione- 17,8-carboxylic acid (XXVII) for methyl 14-methyl-A- nor-Swandmstane 3,11 dione-l7/3-carboxylate (XXV) yields l t-methyl 3 acetoxy-A-nor-A -androstene-11- one-17/3-carboxylic acid (XLVl).

EXAMPLE 60 1 4-methyl-3-acetoxy-A -n0r-A -andr0stene-11 /3-0l- 17/3-carb0xylic acid Following the procedure set forth in Example 54, but substituting 14-methyl-A-nor-5fi-androstane-l 1 ,B-ol-3-one- 17,8-carboxylic acid for methyl 14-methyl-A-nor-Sa-androstane-3,11-dione-17 3-carboxylate (XXV) yields 14-meth yl 3-acetoxy-A-n0r-A -androstene-1 1 /3-ol-17,B-carboxylic acid.

EXAMPLE 61 14 methyl 3 acetoxy A nor A3(5)'9(11) androsiadiene 17/3 carboxylic acid Following the procedure set forth in Example 54 but substituting 14 methyl A nor A901) 5oz androstene 3 one 17/1 carboxylic acid for methyl 14- methyl A nor 5a androstane 3,11 dione 17 3 carboxylate (XXV) yields 14-methyl-3-acetoxy-A-nor- 545L901) androstadiene 17/3 carboxylic acid.

EXAMPLE 62 14 methyl 3 acezoxy A nor A androsteize 17/3 carboxylic acid Following the procedure set forth in Example 54 but substituting 14 methyl A -nor 5a androstane 3 one-17,8-carbcxylic acid for methyl 14-methyl-A-nor-5aandrostane 3,11 clione 17,8 carboxylate (XXV) yields 14-methyl-3-acetoxy-Au1or-A androstene 17B- carboxylic acid.

EXAMPLE 63 Methyl 14 methyl 55 bromo A nor androstane 3,11 clioize 17B carboxylale (XLVII) To a solution of 100 mg. of methyl 14-methyl-3-acetoxy-A-nor-A -androstene 11 one 175 carboxylate (XLV) in 13 ml. of dioxane and 6 ml. of a solution containing 1 ml. of 70% perchloric acid in 100 ml. of water, is added 100 mg. of N-bromoacetamide. After 5 minutes the reaction is stopped by the addition of dilute sodium bisulfite solution until colorless and the methyl 14-methyl- 5/3 bromo A nor androstane 3,11 dione 17B carboxylate (XLVll) is extracted with chloroform. The chloroform-dioxane extract is Washed with dilute sodium bicarbonate and Water, dried over sodium sulfate and the solvents removed in vacuo. The crystalline residue is essentially pure and melts at 159160 with decomposition. The analytically pure sample of methyl I l-methyl- SB bromo A nor androstane 3,11 dione 17/3 carboxylate (XLVH) is obtained by recrystallization max, 5.75 and 5.87 1.

Analysis.-Calcd. for C :H 9O4Bl' (425.35): C, 59.30; H, 6.37. Found: C, 59.30; H, 6.85.

Similarly, following the procedure of Example 63, but substituting N -bromosuccinimide, dibromodimethylhydantoin, or bromine for N-bromoacetamide, yields methyl 14 methyl 5/3 bromo A nor androstane 3,11 dione 17/3 carboxylate (XLVII).

If an N-chloro compound such as N-chlorosuccinimide or an N-iodo compound such as N-iodo acetamide is used in place of N-bromoacetamide in following the procedure of Example 63, there is obtained the corresponding methyl 14 methyl 5/3 chloro A nor androstane 3,11 dione 17/? carboxylate and methyl 14 methyl 5/8 iodo A nor androstane 3,11 dioue 17 8 carboxylate.

EXAMPLE 64 Following the procedure set forth in Example 63 but 7 substituting methyl 14-methyl-3-acetoxy-A-nor-A -an- Methyl 14 methyl 5/? bromo A nor A901) androstene 3 one 17 8 carboxylate Following the procedure set forth in Example 63, but substituting methyl 14 methyl 3 acetoxy A nor A3(5),9(11) androstadiene 17,8 carboxylate for methyl 14 methyl 3 acetoxy A nor A345) androstene 11-one-17/i-carboxylate (XLV) and reducing the quantity of N-bromo-acetamide from mg. to 40 mg. yields methyl 14 methyl 5e bromo A nor A androstene-3-one-17fl-carboxylate.

EXAMPLE 66 Methyl 14 methyl 5/3 bromo A nor androstane 3 one 17/3- carboxylate Following the procedure set forth in Example 63, but substititing methyl 14 methyl 3 acetoxy A -nor A androstene 17/3 carboxylate for methyl 14- methyl 3 acetoxy A nor A androstene 11 one-17/3-carboxylate (XLV) yields methyl 14-methyl-5fibromo A nor androstane 3 one 17/3- carboxylate.

EXAMPLE 67 14 methyl 5/3 bromo A nor androszane 3,11 dioize 17/5 carboxylic acid (XLVHI) Following the procedure set forthin Example 63-, but substituting 14 methyl 3 acetoxy A nor A androstene 11 one 17/3 carboxylic acid (XLVI) for methyl 14 methyl 3- acetoxy A nor A androsteue 1'1 one 1 7/3 carboxylate (XLV) yields 14 methyl 5,8 bromo A nor androstane 3,11 dione-17/3-carboxylic acid (XLVIII).

Similarly, following the procedure of Example 63 but substituting N-chlorosuccinimide or N-iodo acetamide for N-bromo acetamide there is obtained 14-methyl-5/3- chloro A nor androstane 3,11 dione car 35 boxylic acid and 14 methyl 3 acetoxy 5B iodo A nor androstane- 3,11 dione 17f] carboxylic acid, respectively.

EXAMPLE 68 Following the procedure set forth in Example 63 but substituting 14-methyl-3-acetoxy-A-nor-A -androstene- 11,8-ol-l7fl-carboxylic acid for methyl 14-methyl-3-acetoxy-A-nor-A -androstene 11 one 17/8 carboxylate (XLV) yields 14-methyl-5B-bromo-A-nor-androstane-11,8- ol-3-one-17fl-carboxylic acid.

Similarly, following the procedure set forth in Example 63, but substituting N-chlorosuccinimide or N-iodo acetamide for N-bromoacetamide, there is obtained 14- methyl-Sfi-chloro-A-nor-androstane 115 ol 3-one-17ficarboxylic acid and 14-methyl-Sfi-iodo-A-nor-androstane- 11fi-ol-3-one-17,6-carboxylic acid, respectively.

EXAMPLE 69 I4-methyl-5fl-bromo-Amar-A 1)-andr0stene-3-0ne- 17,8-carboxylic acid Following the procedure set forth in Example 63, but substituting 14-methyl-3 acetoxy-A-nor- -androstadiene-17fl-carboxylic acid for methyl 14-methyl-3-acetoxy- A-nor-A -androstene-1l-one 17 ,8 carboxylate (XLV) and decreasing the amount of N-bromoacetamide from 100 mg. to 40 mg. yields 14-methyl-5fl-bromo-A-nor- A -androstene-3-one-17,8-carboxylic acid.

EXAMPLE 7O Following the procedure set forth in Example 63, but substituting 14-methyl-3-acetoxy-Anor-A -androstene- 17,B-carboxylic acid for methyl 14-methyl-3-acetoxy-A- nor-A -androstene 11 one 1718 carboxylate (XLV) yields 14-methyl-5/3-bromo-A-nor-androstane-3-one-17,B- carboxylic acid.

EXAMPLE 71 Into a solution of 50 mg. of methyl 14-methyl-3-acetoxy-A-nor-A -androstene 11 one 17B carboxylate (XLV) in 3 ml. of pyridine and 7 ml. of dioxane maintained at 0 is passed with stirring, a stream of perchloryl fluoride. After 3 minutes excess chloroform is added and the mixture is then extracted with water, dilute acid, sodium bicarbonate solution and again with water. The chloroform-dioxane extract is evaporated to dryness in vacuo and the resulting methyl 14-methyl-5fl-fiuoro-A- nor-androstane-3,11-dione-17/3-carboxylic (XLII) recrystallized from acetone.

EXAMPLE 72 A solution of 62.5 mg. of methyl 14-methyl-5fi-bromo- A+nor-androstane-3,1l-dione-1713 carboxylate (XLVII) and 125 mg. of lithium chloride in 4.5 ml. of dimethyl- "36 formamide is heated on the steam bath for 2 hours. The cooled mixture is diluted with water, extracted with chloroform and the chloroform extract washed thoroughly with water. The chloroform extract is dried over sodium sulfate, evaporated to dryness in vacuo and the 55 mg. residue obtained is separated into the methyl 14-methyl- A-norA -androstene 3,11 dione 17B carboxylate and methyl 14-methyl-A-nor-A -55-androstene-3,1l-dione-17ficarboxylate components by fractional crystallization. Crystallization first from ether then from methanol furnishes, as the more insoluble component, the methyl/14- methyl-A-nor-A -5fl-androstene-3,1l-dione 17,6-carboxylate having the following properties: M.P. 223-224"; M1 +90 (c., .59 in chlf.);

Analysis.Calcd. for 0 1-1 0.; (356.44): C, 74.13; H, 7.92. Found: C, 74.00; H, 8.07.

The ether mother liquors contained the methyl 14- methyl-Anor-A -androstene-3,ll-dione 17fl-carboxylate (L1H) which after recrystallization from methanol has the following properties: M.P. 202-203"; 39 (c., .48 in chlf.);

h3g2} 24:0 my. (e==8,500)

Analysis.Calcd. for C H O C, 74.13; H, 7.92. Found: C, 74.00; H, 8.13.

30 mg. of the material from the mother liquors is dissolved in 1 ml. of benzene and 9 ml. of hexane and chromatographed on 1.6 g. of neutral alumina. Elution with benzene-hexane (1:9) and benzene-hexane (1:3) gives additional crystalline material which furnishes 11 mg. of the pure methyl 14-methyl-A-nor A androstene-3,11- dione-17fl-carboxylate (XLIX).

Similarly, an equimolar amount of lithium bromide may be substituted for the lithium chloride employed in Example 73, without altering the results obtained.

EXAMPLE 74 Methyl 14 methyl A n0r-A -andr0stene-3,1Liliane-175 carboxylate (Lin) and methyl 14-methyl-A -n0r-A -5,8- androstene-3,11-dione-1 7B-carboxylate (XLLX) A solution of 50 mg. of methyl 14-methyl-5fi-bromo- A-nor-androstane-3,11-dione-17B-carboxylate (XLVII) in 1 ml. of collidine is refluxed for one hour. The reaction mixture is dissolved in chloroform and the resulting chloroform solution is extracted with 1 N hydrochloric acid. Concentration of the chloroform extract to dryness furnishes a mixture of methyl 14-methyl-A-nor-A -androstene-3,11-dione-17fi-carboxylate (U11) and methyl 14- methyl-A-nor-N-5 3-androstene-3,11-dione-17fl carboxylate (XLlX), which may be separated into its individual components by fractional crystallization.

EXAMPLE 75 Methyl 14-methyl-A -n0r-A -andr0stene-J1 3-ol-3-one-1 7/3- carboxylate and methyl 14-methyl-A-n0r-A -5fl-aizdr0- stene-11/3-0l-3-0ne-1 7 ,B-carbaxy late Following the procedure set forth in Example 73 but substituting methyl l4-methyl-5fl-bromo-A-nor-andro stane-l1,6-ol-3-one-17 3-carboxylate for methyl 14-methyl- SB-bromo-A-nor-androstane 3,11 dione-17,6-earboxylate (XLVII) yields methyl 14-methyl-A-nor-A -androstene- 1lfi-ol-3-one-17;8-carboxylate and methyl 14-methyl-A nor-A -5,8-androstene-11,6-01-3-one-17fi-carboxylate.

. EXAMPLE 76 Methyl 14-methyl-Amar-A -andr0stadiene-3-0rte-17B- carboxylate and methyl 14-methyl-A-n0r-A -andr0- stadiene-3-one-1 7/3-carb0xylate Following the procedure set forth in Example 73 but substituting methyl 14-methyl-Sfi-bromo-A-nor-A -androstene-3-one-17,8-carboxylate for methyl 14-methyl-5flbromo-A-nor-androstane 3,11 dione 17 3 carboxylate 37 (XLVII) yields methyl 14-methyl-A-nor-A -androstadiene-3-one-17fl-carboxylate and methyl 14-methyl-A-nor- A -androstadiene-3-one-17B-carboxylate.

EXAMPLE 77 Methyl 14-mefl1yl-A -nr-A -andr0stene-3-0ne-1 7 ,B-carboxylate and methyl J4-methyl-A -n0r-A -5B-andr0stene-3- one-1 7 fi-carboxylate Following the procedure set forth in Example 73 but substituting methyl 14 methyl-5,8 bromo-A-nor-androstane- 3-one-17B-carboxylate for methyl 14-methyl-5,B-bromo-A- nor-androstane 3,11 dione-17fl-carboxylate (XLVll) yields methyl 14-methyl-A-nor-A -androstene-3-one-17,8- carboxylate and methyl 14-methyl-A-11or-A -5 fi-androstene-3-one-17(3-carboxylate.

EXAMPLE 78 14-Me2hyl-A-nor A androstene-SJ 1 -di0ne-1 7 ,B-carboxylic acid (LIV) and 14-methyl-A-n0r-A -5fl-androstene-3,11-di0ne-17fl-carb0xylic acid (L) 14-melhyl-A-n0r-A -andr0stene 11/5 0l-3-0ne-17B-carboxylic acid and l4-methyl-A-n0r-A -5,8-andr0stene- 11,8-01-3-0ne-17B-carboxylic acid Following the procedure set forth in Example 73 but substituting 14-methyl-5,B-bromo-A-nor-androstane-11B- ol-3-one-17B-carboxylic acid for methyl 14-methyl-5flbromo-A-nor-androstane-3,11 dione 17B carboxylate (XLVII) yields 14-methyl-A-nor-A -androstene-115-01-3- one-17fl-carboxylic acid and 14-methyl-A-nor-A -5/3-an drostene-l1,8-01-3-one-17B-carboxylic acid.

EXAMPLE 8O 14-methyl-Aaim-A -andr0stadiene-3-0ne 17,8 carboxylic acid and 14-methyl-An0r-A -5fl-andr0stadiene-3-0ne-17,8-carboxylic acid Following the procedure set forth in Example 73, but substituting 14-rnethyl-5fi-bromo-A-nor-A -androstene- 3-one-17fl-carboxylic acid for methyl 14-methy1-5 B-bromc- A-nor-androstane 3,11 dione-lfli-carboxylate (XCVH) yields 14-methyl-A-nor-A -androstadiene-3-one-175- carboxylic acid and 14-methylA-nor-A -55-androstadiene-3-one-17,B-carboxylic acid.

EXAMPLE 81 J4-methyl-A-n0r A andr0stene-3-0ne-17B-carb0xylic acid and 14-methyl-A-nor-A -5fl-andr0stene-3-0ne-l 7(3- carbomlic acid Following the procedure of Example 73 but substituting l4-methyl-5 3-bromo A nor androstane 3 one-17,8- carboxylic acid, for methyl 14-methyl-55-bromo-A-norandrostane-3,1l-dione-l7fi-carboxylate (XLVII) yields 14-methyl-A-nor-A -andr0stene-3-cne-175-carboxy1ic acid and 14-methyl-A-nor-A -5,8-androstene-3-one-17licarbox ylic acid.

3% EXAMPLE s2 Methyl 14-mcihyl-5cc-bromo-A-n0r-andr0stane-3,11- dione-J 7,8-carb0xylate (LI) To a suspension of 210 mg. of methyl 14-methy1-A-nor- 5a-androstane-3,11dione-17,B-carboxylate (XXV) in 2 ml. of glacial acetic acid is added .08 ml. of 6% hydrogen bromide in glacial acetic acid. The crystals dissolve immediately upon addition of the mineral acid. A bromine solution consisting of .2 mmole of bromine and .2 mmole of anhydrous sodium acetate per milliliter of glacial acetic acid is then added (3.3 ml.) followed by the addition of .8 ml. of 6% hydrogen bromide in glacial acetic acid. Decolorization of the bromine occurs immediately accompanied by a precipitation of the methyl 14-methyl-5abromo-A-nor-androstane 3,11 dione 17B carboxylate (Ll). After the addition of 2 ml. of water the crystals are filtered and dried. There is obtained 89 mg. of methyl 14-methyl-5 a-bromo-A-nor-androstane-3, 1 1-dione-17B- carboxylate (LI) which after recrystallization from methanol has the following properties: M.P. 184 and 198 with decomposition; [M (c., .65 in 011113.);

x53; 5.72, 5.75 and 5.88

Optical rotatory dispersion (4.91 mg. in 5 ml. of methanol): first extremum +360, second extremum 1275 Analysis.Calcd. for C H O Br: C, 59.30; H, 6.87. Found: C, 59.48; H, 6.77.

The acetic acid-water filtrate from the methyl 14- methyl 5oz bromo A nor audrostane 3,11 dione- 17fi-carboxylate (Ll) is diluted further with Water, extracted with chloroform and the chloroform extract washed thoroughly with Water, bicarbonate and again with water. The chloroform extract is dried over sodium sulfate, evaporated to dryness and fractionally crys tallized from methanol. There is obtained an additional 65 mg. of the methyl 14'methyl-5a-bromo-A-nor-andro stane-3,11-dione-17fi-carboxylate (L1) in the first crop, and by concentration of the mother liquors, 17 mg. of methyl l4 methyl 55 bromo A nor androstane- 3,11-dione-17B-carboxylate (XLVII), having an MP. of This latter material was identifi d by mixture melting point and infrared comparison. Optical rotary dispersion: first extremum [M 506.

EXAMPLE 83 M etlz yl l4-methyl-5a-bromo-A -n0r-aizdr0stane-3,1 1- diorze-l' 7,8-carb0xylafe (LI) Following the procedure set forth in Example 82, but substituting methyl 14- nethyl-A-nor-SB-androstane-3,11- dione-17fl-carboxylate (XXVI) for methyl l l-methyl-A- nor 5o: androstane 3,11 dione 17B carboxylate (XXV) yields methyl 14-methyl-5a-bromo-A-nor-androstane-3,11-dione-17B-carboxylate (LI) EXAMPLE 84- 14-111 ethyl-5a-br0m o-A mar-androstaned, l1 -dione- 1713-carb0xyiic acid (LII) EXAMPLE 85 M' ethyl 1 4 -m ethyl-A mar-M-androstene-S ,1 J -di0nel 7fl-carb0xy late (L111) 7 'A solution of mg. of methyl 14-methyl-5a-bromo- A-nor-androstane-3,1l-dione-17B-carboxylate (LI) and 1.5 g. of lithium bromide in 13.5 ml. of dimethylformamide is heated on the steam bath for 2 hours. The resulting mixture is diluted with water, the mixture extracted with chloroform and the chloroform extract washed with Water and sodium bicarbonate, dried over sodium sulfate and evaporated to dryness in vacuo. The residue weighing 135 mg. yields on crystallization from methanol 86 mg. of pure methyl l4-methyl-A-nor-A androstene-3,11-dione-17 3-carboxylate (L111) melting at 202-203;

)djfig, 240 mp. (e=9,600).

EXAMPLE 86 14-111 ethyl-A -nI'A -andr0stene-3,1l -di0ne-1 75- carboxylic acid (LIV) A solution of 16 mg. of methyl l4-methyl-A-nor-A androstene-3,11-dione-17fi-carboxylate (Llll) in 3.75 ml. of .7 N methanolic potassium hydroxide and 2.5 ml. of Water that has been refluxed and cooled underhelium is refluxed under a blanket of helium for 7 hours. The mixture is then acidified with glacial acetic acid, diluted with Water and extracted with chloroform. The cloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue after recrystallization from methanol yields 14 methyl A nor A androstene 3,11 dionel7,8-carboxylic acid (LIV) having the following properties: M.P. 275285;

M13241 my. (e=7,600); REE; 5.75, 5.86 and 6.06 1

EXAMPLE 87 14-methyl-A -n0rA -5B-andr0stene-3,1 1 -di 011e- 17,6-carboxylic acid (L) Following the procedure set forth in Example 86 but substituting methyl 14-methyl-A-nor-N-Sfi-androstene- 3,11-dione-17B-carboxylate (XLIX) for methyl 14-methyl A nor A androstene 3,11 dione 17 8 carboxylate (LIII) yields 14-methyl-A-nor-A 5,B-androstene- 3,11-dione-17B-carboxylic acid (L).

EXAMPLE 88 l 4-m ethyl-A -n0J"A -andr0stene-1 l 6-01-3 -0nel 7 3- carboxylic acid Following the procedure of Example 86 but substituting methyl 14-methyl-A-nor-M-androstene-11,8-01-3-one- 17,8-carboxylate for methyl 14-methyl-A-nor-A -androstem-3,11-dione-l7 3-carboxylate (LIII) yields 14-methyl- A-nor-M-androstene-l 1,8-ol-3-one-17fl-carboxylic acid.

EXAMPLE 89 Following the procedure of Example 86 but substituting methyl 14-methyl-A-nor-A -5fi-androstene-11,8-01-3- one-17fl-carboxylate for methyl l4-methyl-A-nor-A androstene-3,11-dione-17fl-carboxylate (Llll) yields 14- methyl A nor A 5 3 androstene llfl ol 3- one-17/8-carboxylic acid.

EXAMPLE 90 14-mefhyl-A mar-A -androstadierze-3-one- 1 7-carb0xylic acid Following the procedure set forth in Example 86 but substituting methyl 14 methyl A nor A5301) androstadiene-3-one-17fi-carboxylate for methyl 14-methyl- A nor A androstene 3,11 dione 17,6 carboxylate yields 14 methyl A nor A5301) androstadiene 3-one-17fl-carboxy1ic acid.

EXAMPLE 91 J4-methyl-A-nofiA -5fl-andr0sladiene-3-0ne- 17/3-carb0xylic acid Following the procedure set forth in Example 86 but substituting methyl 14-methyl-A-nor-A -Sfl-androstene-3-one-17fi-carboxylate for methyl l4-methyl-A-nor- 49 A androstene 3,11- dione 17B carboxylate (LIII) yields 14 methyl A nor A1301) 5,6 androstadiene- 3-one-l7fi-carboxylic acid.

EXAMPLE 92 14-methyl-A-n01 A -andr0stene-3-0ne-1 7 ,8-

carboxylic acid Following the procedure set forth in Example 86 but substituting methyl 14 methyl A nor A androstene-3-one-17B-carboxylate for methyl 14-methyl-A-nor- A -androstene-3,11-dione-17B-carboxylate (LIII) yields 14-methyl-A-nor-A -androstene-3-one-17;?-carboxylic acid.

EXAMPLE 93 1 4-mctlz yl -A -n 0rA -5 B-amiroslene-3 -one-] 7 ,8-

carboxylic acid Following the procedure set forth in Example 86 but substituting methyl 14 methyl A nor A 5 3 androstene-3-one-17B-carboxylate for methyl 14-methyl-A- nor A androstene 3,11 dione 175 carboxylate yields 14 methyl A nor A 5B androstene 3- one17,8-carboxylic acid.

EXAMPLE 94 Methyl 14-methyl-3,3-ethylenedioxy-A-nor-A -andr0stene- 11-0ne-l7fl-carb0xylate (CXXIV) and methyl 14-methyl-3,3-etlzylenedi0xy-A-n0r-A androstene-lLone-1713- carboxylate (CXXVI) To a stirred mixture of 133 ml. of benzene, 20 ml. of ethylene glycol and 266 mg. of p-toluenesulfonic acid, which has been refluxed for 1 hour with the aid of a Dean-Stark separator is added 200 mg. of methyl-A-nor- A -androstene-3,1l-dione-l7fi-carboxylate (H11) and the resulting mixture is continued at reflux for 6 hours. The mixture is then cooled, neutralized rapidly by the addition of excess sodium bicarbonate, diluted with water and the layers separated. The aqueous layer is washed again with benzene and the combined benzene extracts dried over sodiumsulfate. Evaporation of the solvent in vacuo produces a crystalline residue, which on recrystallization from methanol furnishes 103 mg. of the pure methyl 14 methyl 3,3-etl1ylenedioxy-A-nor-A -androstene-11- one-l7fi-carboxylate (CXXIV) possessing the following properties: needles M.P. 143-144"; [o:.] +153 (0., .83 in chlf.);

REE; 5.79, 5.87.

Analysis.Calcd. for C H O (388.49): C, 71.10; H, 8.30. Found: C, 71.11; H, 8.30.

Fractional crystallization of the mother liquors produces the isomeric methyl 14-methyl-3,3-ethylenedioxy- A-nor-A -androstene-1l-one-l7fi-carboxylate of the following properties: prisms melting at 150-151"; [11],; +25;

EXAMPLE 95 M ethyl 14-metl1yl-3,3-elhylencdioxy-A-nor-5fi-androstane- 1 1 -0lze-1 7,8-carboxylate (CXLVIII) Following the procedure set forth in Example 94 but substituting methyl 14-methyl-A-nor-SB-androstane-3,11- dione-17,B-carboxylate (XXVI) for the methyl 14-methy1- A-nor-A -androstene-3,11-dione-17f3 carboxylate (L111) there is obtained methyl 14-methyl-3,3-ethylenedioxy-A- nor-Sfi-androstane-l Lone-176 carboxylate (CXLVIH), which after crystallization from methanol, has the following properties: M.P. 189-190"; [M +67 (c., .6 in chlf.);

5.77 and 5.90;;

' 'Analysis-Calcd. for C H O C, 70.74; H, 8.72 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS HAVING THE FORMULAE
 9. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STERIODS HAVING THE FORMULAE 